1,720,963 research outputs found
The sigma enigma. 3D homology modeling, computer-assisted drug design, 3D pharmacophore-guided docking, MM/PBSA scoring, in silico/in vitro alanine scanning mutagenesis, and functional assay to unveil the sigma-1 receptor hidden secrets.
No full textOriginally considered an enigmatic receptor, the sigma1 receptor has recently been identified as a unique ligand-regulated protein. Since its discovery, many studies have shown the potential of sigma1 receptor ligands for the treatment of various diseases of the central nervous system (CNS). However, to date almost no information are available not only the interaction of ligands but also the differences in the interactions of agonists and antagonists with the sigma1 receptor protein have not yet been determined. Under these gloomy perspectives, in this work we embarked in the following, very ambitious task: we i) designed and synthesized novel ligands with high affinity and selectivity for the 1 receptor protein based on our unique in-house developed 3D model of the receptor, and a combination of 3D pharmacophore-based docking (Figure1) and MM/PBSA free energy of binding scoring (1); ii) determined the sigma1 affinity of the ligands in receptor binding studies with radioligands; iii) parallel in silico and experimental site directed mutagenesis experiments yielded a preliminary molecular-based rationale for the agonistic and antagonistic effects of the ligands; These results afforded a dramatic improvement in the understanding of the functions and roles of the sigma1 receptor. This, in turn, will foster the development of news drugs aimed at treating frequent and important human illness such as Alzheimer’s disease, depression, anxiety and pain
The long and winding road of the c-Kit juxtamembrane domain
No full text1. Introduction
Gastrointestinal stromal tumors (GISTs) are the most common primary
mesenchymal tumors of the human gastrointestinal tract, and most GISTs express
constitutively activated c-Kit oncoproteins.1 Several clinical studies demonstrate that
tumors showing mutation in exon 11 (encoding the juxtamembrane domain) respond
better than all the other GIST tumoral genotypes. The KIT wild-type sequence folds
into a series of β- hairpin structures. The structure, stability and folding of β- hairpin
structures has been the object of many studies. Recently, several works reported
successful simulations of reversible hairpin folding of different peptides in explicit
water at native folding conditions through self-guided molecular dynamics (SGMD)
simulations.2
2. Results and Discussion
Using SGMD simulations we study the reversible
folding events of wild-type and mutated c-Kit JMX
domains. The mutations considered were the two-residue
deletion Δ559-560 (Fig.1) and the missense point mutation
V560G, both known to constitutively activate c-Kit in
GISTs. This work aids to support the clinical evidence of a
better response to Imatinib, an ATP-competitive TKIs, of
KIT exon 11 mutant in comparison with WT receptor and
provides the first atomistic description of the output of
several clinical studies of GIST treated with Imatinib
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib
No full textGastrointestinal stromal tumors carry in about 85% of the cases activating mutations in KIT gene. Generally only one KIT mutation is found in primary tumors and the majority of mutations affecting KIT exon 11 is sensitive to Imatinib. We report upon a GIST case harboring a double-mutant KIT gene at exon 11, which expresses a receptor bearing the known activating W557G mutation and a newly discovered missense Y578C alteration. The relative affinities for ATP and Imatinib of each single (W557G, Y578C) and double (W557G/Y578C) mutant KITs were predicted by in silico studies (computer-based molecular simulations), and compared with those obtained for known Imatinib sensitive and resistant KIT mutants. In parallel, biochemical analysis of the single and double KIT mutants expressed in mammalian cells was performed. Both the in-silico/in-vitro investigations showed constitutive activation and sensitivity to Imatinib of the yet mentioned Y578C mutation as well as of the double mutant, providing evidence that the concomitant presence of the W557G and Y578C mutations does not affect Imatinib response compare to the single mutations, in line with what observed in Imatinib treated patient
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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